WO2022179238A1

WO2022179238A1 - Btk and/or btk c481s small molecule inhibitor and use thereof

Info

Publication number: WO2022179238A1
Application number: PCT/CN2021/135698
Authority: WO
Inventors: 谢玲芝; 乔丹丹; D达斯; 洪健
Original assignee: 安润医药科技（苏州）有限公司
Priority date: 2021-02-26
Filing date: 2021-12-06
Publication date: 2022-09-01
Also published as: CN112574200B; US20240018150A1; CN112574200A; EP4299575A1; JP2024507909A

Abstract

Provided is a compound having the structure shown in formula I, or an enol compound, pharmaceutically acceptable salt, deuterium substituted derivative, hydrate or solvate, active metabolite, polymorph, ester, optical isomer or prodrug thereof, a pharmaceutical composition comprising the compound having the structure shown in formula I, and a use in the preparation of a drug as a Bruton's tyrosine kinase (BTK) inhibitor or selective for a BTK mutant (C481S) for the prevention or treatment of immune-related diseases, autoimmune diseases, or cancer.

Description

As small molecule inhibitors of BTK and/or BTK C481S and uses thereof

Technical field:

The present invention relates to novel compounds, more particularly to compounds represented by formula I or pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, esters, optical isomers, as kinase inhibitors body or prodrug and/or its pharmaceutical composition. In particular, the present invention relates to Bruton's tyrosine kinase (BTK) inhibitors and/or including BTK(C481S) mutants.

Background technique:

Bruton's tyrosine kinase (BTK) signaling and response to B cell receptor (BCR)-mediated maintenance of the B cell repertoire (Hunter, cell, 1987 50, 823-829) and early B cell development and mature B cells Activated regulators are essential. Signals control a range of effector responses through the BCR, including activation, proliferation, and differentiation of mature antibody-producing cells. BTK is also expressed in other hematopoietic cells, such as monocytes, macrophages, and mast cells, and it regulates certain immune responses, such as TNF production through Fc receptor stimulation. Therefore, TNF-mediated inflammation may be modulated by small-molecule BTK inhibitors. Bruton's tyrosine kinase (BTK) plays an important role in the B cell receptor (BCR) and Fcγ receptor (FcγR) signaling pathways, regulating the activation, proliferation, differentiation and survival of B cells. Abnormal BTK function has been observed in B cell-derived malignancies, including mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL) , Walden's Macroglobulinemia (WM), and Multiple Myeloma (MM) (Nature. 2010;463(7277):88-92). Therefore, BTK is considered to be an important therapeutic target for the treatment of B-cell malignancies and autoimmune diseases (Expert Opinion on Investigational Drugs. 2017;26(8):909-915). Ibrutinib was the first FDA-approved treatment for Mantel cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) and Waldenstrom macroglobulinemia (WM) (New England Journal of Medicine. 2013; 369(6):507-516) irreversible BTK inhibitors (Future Oncology. 2014;10(6):957-967). Ibrutinib can effectively inhibit the proliferation of certain types of DLBCL. The mechanism of action of ibrutinib is to covalently cross-link with the thiol structure at position 481 of BTK protein in cells, thereby depriving the function of downstream signaling proteins of BTK phosphorylation and exerting an anti-cell proliferation effect. Despite the significant clinical efficacy of ibrutinib in B-cell malignancies, cases with primary and secondary resistance have a poor prognosis and limited treatment options. In addition, ibrutinib has strong inhibitory activity against BTK kinase, and the drug itself has strong off-target effects and causes many side effects, such as diarrhea and skin rash, resulting in loss of natural killer cell function and causing coagulation defects. Most patients with CLL who develop resistance to irreversible BTK inhibitors such as ibrutinib develop the BTK-C481S mutation. It has been reported that 80% of CLL relapsed patients will have the C481S mutation (Maddocks KJ, et al. JAMA Oncol. 2015; 1:80-87). Another research group reported clinical progression in about 20% of ibrutinib patients and C481S mutation in 85% by the fourth year (Journal of Clinical Oncology Vol 35, number 13, 2017, page 1437). Furthermore, these mutations were detected within an average of 9 months before relapse. BTK kinase C481S mutation has been reported to result in significantly reduced ibrutinib sensitivity. BTK has emerged as a novel molecular target for the treatment of B-cell lymphomas, leukemias and autoimmune diseases (Shinohara et al, Cell 132(2008) pp794-806; Gilfillan et al, Immunological Reviews 288(2009) pp 149-169; Davis et al, Nature, 463 (2010) pp88-94). Targeting BTK with small-molecule inhibitors may have advantages over biological therapies for RA, such as modulating B cell responses and/or activation, while better maintaining desirable immune competence (Franks, S.E., et al., Current Opinion in Immunology (Franks, S.E., et al., Current Opinion in Immunology ( 2016), 43:39-45).

Inhibition of BTK with small molecule inhibitors has the potential to treat immune disorders, cancer, cardiovascular disease, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders. Therefore, the search for novel small-molecule compounds with BTK inhibitory activity and inhibitors of BTK(C481S) mutants is still the focus and need of future research.

As an important aspect of the present invention, the present invention provides a compound. After intensive research, the inventors found that the compounds represented by formula I have inhibitory activity against BTK, especially the BTK C481S mutant. Compounds of formula I or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites or pharmaceutically acceptable salts or prodrugs, useful in the treatment of cancer, allergic Diseases, autoimmune diseases, inflammatory diseases, etc., especially the treatment of B-cell lymphoma and leukemia, has excellent therapeutic effects for cancer patients who are resistant to existing drugs.

Summary of the invention:

The present invention relates to novel potent and selective BTK inhibitors rationally designed to inhibit WT BTK and/or to inhibit C481S mutant BTK.

Herein, the present invention provides compounds of formula I, wherein R, G, W ¹ , W ² , W ³ , X, Y are as defined herein, and enol esters, pharmaceutically acceptable salts, solvates, and combinations thereof things,

in:

R is independently selected from substituted or unsubstituted alkyl, alkenyl, alkyl substituted or unsubstituted alcohol, alkyl substituted or unsubstituted amine, substituted or unsubstituted four to seven membered carbocycle, substituted or unsubstituted Substituted four- to seven-membered carbocyclic rings with heteroatoms including, but not limited to, N, S, O atoms.

Further, R is independently selected from substituted or unsubstituted C ₁ -C ₆ alkyl, C ₂ -C ₄ alkenyl, alkyl substituted or unsubstituted C ₁ -C ₆ alcohol, alkyl substituted or unsubstituted Substituted C ₁ -C ₆ amines, substituted or unsubstituted four- to seven-membered carbocycles, substituted or unsubstituted four- to seven-membered carbocycles with heteroatoms, including but not limited to N, S, O atoms.

Wherein the substituent is selected from amine group, ester group, carboxyl group, hydroxyl group, amide group (including N-attachment and C-attachment), sulfonyl group, sulfonamide group, C ₁ -C ₄ alkyl group, C ₁ -C ₄ amine group, C ₁ -C ₄ alcohols, C ₁ -C ₄ ethers.

G is independently selected from five- or six-membered aryl, substituted aryl, heteroaryl, substituted heteroaryl, biphenyl, carbocycle, heteroatom-containing carbocycle, unsaturated carbocycle.

W ¹ , W ² , and W ³ are independently selected from CH or N satisfying the valence bond theory.

X is independently selected from O, N, NH

Y is independently selected from the list below, but is not limited to

When Y is absent, there is a chemical bond between the G unit and the heteroaryl ring.

The present invention also provides methods of using the inventive compounds of general formula I, and pharmaceutically acceptable salts thereof, in admixture with pharmaceutically acceptable diluents or carriers.

Also provided herein is a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof as defined herein.

The object of the present invention is to provide a small molecule compound with BTK inhibitory activity. The compounds of the present invention can be used to treat patients who are resistant/refractory to first generation BTK inhibitors (eg ibrutinib and acalatinib), especially patients with BTK C481S mutation. The present invention provides compounds represented by the following formula I, or pharmaceutically acceptable salts, or stereoisomers or tautomers thereof, and pharmaceutically acceptable salts, hydrates or solvates thereof; pharmaceutically acceptable salts thereof Acceptable carriers, or stereoisomers or tautomers thereof, and pharmaceutically acceptable salts, hydrates or solvates thereof. The use of the pharmaceutical composition according to the second aspect of the present invention is characterized by the manufacture of a medicament for the prevention and/or treatment of abnormal activation of BTK and diseases associated with abnormal activation of BTK mutants (eg C481S).

The compounds of the present invention can be used to treat patients with diseases such as autoimmune diseases, inflammatory diseases or cancers, including but not limited to B cell-derived malignancies (MCL), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL) ), non-Hodgkin's lymphoma (NHL), in Waldenstrom's macroglobulinemia (WM) and multiple myeloma (MM).

Detailed description and examples:

Compounds of the invention are described by the general structural formula I, and examples, sub-examples, and structures of the general formulae Ia, Ib, Ic, Id, Ie, If are disclosed herein. Abbreviations used herein have conventional meanings in the fields of chemistry and biology. As used herein, the following definitions and terms shall apply unless otherwise indicated.

"R" and "S" describing isomers are descriptors of the stereochemical configuration of asymmetrically substituted carbon atoms. The naming of asymmetrically substituted carbon atoms as "R" or "S" is accomplished by applying the Cahn-Ingold Prelog precedence rule, which is also known to those skilled in the art and described in the International Union of Pure and Applied Chemistry (lUPAC) Nomenclature for Organic Chemistry. Section E, Stereochemistry.

The term C _ij as used herein means that the moiety has ij carbon atoms. For example, _C1-10 alkyl means that the alkyl unit has any number between 1 and 10 carbon atoms.

"Alkyl" or "alkane," as used herein, refers to a fully saturated straight, branched, or cyclic hydrocarbon chain, or a combination thereof. Alkyl groups may be saturated, monounsaturated or polyunsaturated, which may include divalent or polyvalent groups, with the indicated number of carbon atoms (ie, _C1 - _C10 refers to one to ten carbon atoms). In certain embodiments, the alkyl group contains 1-6 carbon atoms. In certain embodiments, the alkyl group contains 1-4 carbon atoms. In certain embodiments, the alkyl group contains 1-3 carbon atoms. In other embodiments, the alkyl group contains 2-3 carbon atoms, and in other embodiments, the alkyl group contains 1-2 carbon atoms. In certain embodiments, the term "alkyl" or "alkane" refers to a cycloalkyl group, also known as a carbocycle. Examples of saturated hydrocarbon groups include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl , n-octyl, cyclohexyl, cyclohexylmethyl, etc. The unsaturated alkyl group is an alkyl group having one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-prenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 , 4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butenyl and higher homologues and isomers. Alkyl groups are optionally substituted with one or more halogen atoms. For example, the term "fluoroalkyl" refers to an alkyl group as defined above wherein one or more hydrogen atoms are replaced with fluorine atoms.

The term "alkoxy" refers to a straight or branched chain alkoxy group having the indicated number of carbon atoms. For example, C _1-6 alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, and the like.

_The term "alkenyl" by itself or as part of another substituent refers to a divalent group derived from an alkyl group such as, but not limited to, _{-CH2CH2CH2CH2-} , _-CH2CH ₌ _CH2- _, -CH ₂ C≡CCH ₂ -, -CH ₂ CH ₂ CH(CH ₂ CH ₂ CH ₃ )CH ₂ -, the alkyl group (or alkylene group) usually has 1 to 24 carbon atoms, and is preferred in the present invention A group having 10 or fewer carbon atoms.

The term "alkynyl" refers to a carbon chain containing at least one carbon-carbon triple bond, which may be straight or branched, or a combination thereof. Examples of alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptyl, and the like. Alkynyl groups are optionally substituted with one or more halogen atoms.

The term "cycloalkyl" refers to a monocyclic or bicyclic saturated carbocyclic ring, each ring having 3 to 10 carbon atoms. A "fused analog" of a cycloalkyl group refers to a monocyclic ring fused to an aryl or heteroaryl group where the point of attachment is on the non-aryl moiety. Examples of cycloalkyl and fused analogs are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, decalinyl, indenyl, and the like. The cycloalkyl is optionally substituted with one or more halogen atoms. The term "heteroalkyl" by itself or in combination with another term refers to a stable straight hydrocarbon group consisting of at least one carbon atom and at least one heteroatom selected from O, N, P, Si, and S, or a cyclic hydrocarbon group, or a combination thereof. Chain or branched, wherein the nitrogen, phosphorus or sulfur atoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized. The heteroatoms O, N, P, S, and Si can be placed anywhere within the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ -, -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -Si( _CH3 ) ₃ , _-CH2 -CH=N- _OCH3 , -CH=CH-N( _CH3 ) _-CH3 , -O- _CH3 , -O- _CH2 - _CH3 and -CN . Up to two or three heteroatoms may be consecutive. For example, _-CH2 -NH- _OCH3 and _-CH2 -O-Si( _CH3 ) ₃ .

The term "cycloalkoxy" refers to a cycloalkyl group as defined above bonded to an oxygen atom, eg, cyclopropoxy.

Similarly, the term "heteroalkenyl" by itself or in combination with other terms refers to divalent groups derived from heteroalkyl groups such as, but not limited to, _-CH2 - _CH2 -S- _CH2 -CH2- _and- _CH2 -S- _CH2 - _CH2 - _CH2 _- NH-CH2-. For heteroalkenyl groups, the heteroatoms may be located at either or both ends of the chain (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the linking group formula is written does not indicate the orientation of the linking group. For example, the formula -C(O) or '- means -C(O) or '- and -R'OC(O)-. As used herein, heteroalkyl groups include those groups attached to the remainder of the molecule through a heteroatom, eg, -C(O)R', -C(O)NR', -NR'R', -OR', -SR' and/or -SO ₂ R'. Where reference is made to "heteroalkyl" and later to a specific heteroalkyl such as -NR'R", it should be understood that the terms heteroalkyl and -NR'R" are not repetitive and are not mutually exclusive. Instead, these specific heteroalkyl groups are referenced for clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups such as -NR'R".

As used herein, the term "substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group substituted with 1 to 5 (eg, 1 to 3) substituents. The substituents are the same as those defined for substituted cycloalkyl.

"Aromatic ring" or "aryl" refers to an aromatic carbocyclic moiety having one or more closed rings. Examples include but

Not limited to phenyl, naphthyl, anthracenyl, benzanthryl, biphenyl and pyrenyl.

"Heteroaryl" means a monocyclic or bicyclic moiety containing at least one heteroatom selected from oxygen, nitrogen or sulfur, at least one of the rings, wherein at least one of the rings is aromatic, and wherein The one or more rings may be independently fused and/or bridged. Examples include, but are not limited to, pyridyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, indolyl, furanyl, thienyl, quinoxalinyl, indolazolyl, thieno[2,3 -c]pyrazolyl, benzofuranyl, thienothiazolyl, benzothiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl , tetrazole, furanyl, triazinyl, thienyl, pyrimidinyl, pyridazinyl, pyridazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothienyl , furan and [2,3-b]pyridyl, quinolinyl, indolyl, isoquinolinyl, etc.

Unless otherwise indicated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo( _C1 - _C4 )alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like

Optical Isomers, Diastereomers, Geometric Isomers, and Tautomers: Some of the compounds of Formula I may contain one or more ring systems, and thus cis and trans isomers may exist. The present invention is intended to cover all such cis and trans isomers. The inclusion of olefinic double bonds, unless otherwise specified, is meant to include both E and Z geometric isomers.

Some of the compounds described herein may possess one or more asymmetric centers, and they are available as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers.

Some of the compounds described herein may have different attachment sites for the hydrogen atom, which are known as tautomers. An example of this might be the ketones and their enol forms known as keto-enol tautomers. Both individual tautomers and mixtures thereof are included in the compounds of formula I.

Compounds of formula I can be isolated as diastereomeric enantiomers, for example, by crystallization from a suitable solvent such as methanol or ethyl acetate or mixtures thereof. A pair of enantiomers thus obtained can be separated into individual stereoisomers by conventional methods, eg, using optically active amines or acids as resolving reagents or in chiral HPLC columns.

Any enantiomer of a compound of general formula I can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.

In addition, compounds of formula I may also include a range of stable isotope labeled analogs. For example, one or more protons in a compound of formula I can be replaced by a deuterium atom, thereby providing deuterated analogs with improved pharmacological activity.

"Pharmaceutically acceptable salt" refers to an acid or base salt of a compound of the present invention which has the desired pharmacological activity and is not biologically or otherwise undesirable. Salts may include, but are not limited to, acetate, adipate, benzoate, citrate, camphorate, camphorsulfonate, digluconate, lauryl sulfate, ethanesulfonate, Fumarate, Glucoheptanoate, Glycerophosphate, Hemisulfate, Heptanoate, Caproate, Hydrobromide Hydrochloride, Hydroiodide, 2-Hydroxyethane Sulfonate, Lactate, Maleic acid, oxalic acid. It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features (eg, embodiments) specifically described below can be combined with each other to form new or preferred technical solutions.

In embodiments of the invention disclosed herein are compounds of formula I, wherein R, G, W ¹ , W ² , W ³ , X and Y are defined herein, and pharmaceutically acceptable salts, solvates and compositions thereof,

in

R is independently selected from substituted or unsubstituted alkyl, alkenyl, alkyl substituted or unsubstituted alcohol, alkyl substituted or unsubstituted amine, substituted or unsubstituted four to seven membered carbocycle, substituted or unsubstituted A four- to seven-membered carbocyclic ring with heteroatoms, including but not limited to N, S, and O as heteroatoms.

X is independently selected from O, NR, NH, CO

W ¹ , W ² , W ³ are independently selected from CH or N satisfying the valence bond theory

Y is independently selected from ketocarbonyl, methylene, difluoromethyl, and the structures in the following table, but is not limited to the following structures:

When Y is absent, there is a bond between the G unit and the heteroaryl ring of the parent nucleus selected in formula I.

R-X are independently selected from but not limited to the following structures:

G is independently selected from 5 or 6 membrane aryl, substituted aryl, heteroaryl, substituted heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, biphenyl, wherein aryl and Heteroaryl is optionally substituted with R ¹ , R ² or R ³ . Further Gs are specified and independently selected but not limited to the following structures:

Wherein, R ¹ , R ² and R ³ are independently selected from hydrogen, amine, hydroxyl, halogen, C ₁ -C ₆ alkyl, any one or more alkoxy substituted C ₁ -C ₆ alkoxy, C ₁ - _C6 haloalkyl, _C1 - _C6 haloalkoxy, amine, alkylamine, amide, ether, thioether, containing 1 or 2 4- to 6-membered rings and carbocycles, including N, O is heterocyclic Atoms of heterocarbocycles, phenoxy, substituted phenoxy. The middle ring backbone atoms together form a C ₃ -C ₈ carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the heterocyclic heteroatom is selected from: S, O or NR; R is H, C ₁ -C ₁₀ alkyl, C ₃ - C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl.

wherein M is independently selected from -O-, -NH-, _-CH2- , -CO-, -CONH-, -S-, _-SO2- .

In some embodiments, the compounds are of Formula Ia, Ib, Ic, and alkenoate salts thereof, or pharmaceutically acceptable salts and solvates thereof.

in

R is independently selected from C _1-10 substituted or unsubstituted alkyl, alkenyl, alkyl or substituted alcohol, alkyl or substituted amine, substituted or unsubstituted four to seven membered carbocyclic ring , substituted or unsubstituted four- to seven-membered carbocyclic rings with heteroatoms, including but not including N, S, O atoms as heteroatoms.

X is independently selected from O, NR, NH, CO

Y is independently selected from, but is not limited to, ketocarbonyl, methylene, difluoromethyl, and the structures in the following table:

When Y is absent, there is a chemical bond between the G unit and the heteroaryl ring of the parent nucleus selected in formula I.

R-X are independently selected from the following list, as described in Equation I.

G is independently selected from 5- or 6-membered substituted or unsubstituted aryl, substituted heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, biphenyl, wherein aryl and heteroaryl are optionally Substituted by R ¹ , R ² or R ³ .

Further Gs are set forth and independently selected from the following structures, as described for Formula I, but not limited thereto:

Wherein, R ¹ , R ² or R ³ are independently selected from hydrogen, amine, hydroxyl, halogen, C ₁ -C ₆ alkyl, one or more alkoxy optionally substituted C ₁ -C ₆ alkoxy, C ₁ - _C6 haloalkyl, _C1 - _C6 haloalkoxy, amines, alkylamines, amides, ethers, thioethers, heterocycles containing one or two 1- to 6-membered rings or carbocycles, containing N, O Heterocarbocycles that are heteroatoms, phenoxy, substituted phenoxy. The middle ring skeleton atoms together form a C ₃ -C ₆ carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the heteroatom of the heterocyclic ring is selected from: S, O or NR; R is H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl.

In some embodiments, the compounds are of formula Id, Ie, If, and alkenoate salts thereof, or pharmaceutically acceptable salts and solvates thereof.

in,

R is independently selected from C _1-10 substituted or unsubstituted alkyl, alkenyl, alkyl substituted or unsubstituted alcohol, alkyl substituted or unsubstituted thiol, substituted or unsubstituted four- to seven-membered carbocyclic ring, Substituted or unsubstituted four to seven membered carbocyclic rings with heteroatoms, including but not limited to heteroatoms N, S, O.

R independently chooses but is not limited to the following structures:

G is independently selected from 5- or 6-membered substituted or unsubstituted aryl, substituted aryl, substituted heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, biphenyl, wherein aryl and Heteroaryl groups can be optionally substituted with R ¹ , R ² or R ³ . wherein, R ¹ , R ² or R ³ are independently selected from hydrogen, amine, hydroxyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy optionally substituted by one or more alkoxy groups , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amines, alkylamines, amides, ethers, thioethers, heterocycles containing one or two 1- to 6-membered rings or carbocyclic rings, containing N , O is a heterocarbocycle of a heteroatom, phenoxy, substituted phenoxy. The middle ring skeleton atoms together form a C ₃ -C ₆ carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the heteroatom of the heterocyclic ring is selected from: S, O or NR; R is H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₂₀ aryl.

G is independently selected from the list of formula I, but is not limited thereto.

Examples 1-90:

Overview

Column chromatography was performed using silica gel (100-200) and various eluents as described above. Solvent removal was performed using a Buchii rotary evaporator or Genevac centrifugal evaporator. Preparative LC/MS was performed using a Waters autopurifier and a 19x100mm XTerra 5 micron MS CI8 column under acidic mobile phase conditions. NMR spectra were recorded with a Varian 400MHz spectrometer. When the term "inert" is used to describe a reactor (eg, reaction vessel, flask, glass reactor, etc.), it means that the air in the reactor has been replaced by an inert gas (eg, nitrogen, argon, etc.) that is substantially free of water or dryness )replace.

The following abbreviations are used here:

Definitions: The following abbreviations have the following meanings:

HATU: 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluracil hexafluorophosphate

DPCI: N,N'-diisopropylcarbodiimide

DIEA: N,N-Diisopropylethylamine

TEA: Triethylamine

DMAP: 4-Dimethylaminopyridine

DMF: N,N-Dimethylformamide

NMP: N-methylpyrrolidine

THF: Tetrahydrofuran

DCM: dichloromethane

TFA: trifluoroacetic acid

DMA: N,N-Dimethylacetamide

TLC: Thin Layer Chromatography

TMOF: Trimethyl orthoformate

PTSA: p-toluenesulfonic acid

NIS: N-Iodosuccinimide

eq: equivalent

mmol: Hamol

mole: mole

mL: milliliter

L: liter

MHz: Megahertz

δ: chemical shift

DMSO-d6: Deuterated Dimethyl Sulfoxide

Hrs,hr,h,hours: hours

Ms: Mass Spectrometry

m/z: mass-to-charge ratio

plan 1:

Compounds (8a-8n, Table 1) were prepared according to Scheme 1 and following the procedure for the preparation of 8a.

(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4- Preparation of phenoxyphenyl)methanone (8a)

Step 1: Under nitrogen protection, the DMF mixed solution of compound 2a (25.5g, 0.27mol) was cooled to about 0°C, and NaH (18.0g, 0.452mol, 60% in oil) was added to the above mixed solution in batches And stirring for 30 minutes, compound 1a (35 g, 0.226 mol) was added to the above mixed solution in batches, the reaction mixture was warmed to room temperature and stirred for 4 hours, TLC monitoring the reaction showed that compound 1a was completely consumed, the reaction mixture was used at 0 ° C. Quenched with saturated ammonium chloride solution, extracted with ethyl acetate (200 ml x 3), the organic phases were washed with water and brine and combined, dried over anhydrous sodium sulfate and evaporated to dryness to give crude product (52 g, 100%). The purity of the product 3a is sufficient for the next step of synthesis, and no further purification is required. ¹ H NMR (DMSO-d6, 400MHz): δ=7.95(d,1H), 7.52-7.48(m,2H), 7.34-7.30(m,2H), 7.21-7.19(m,2H), 7.05-7.02 (m,1H).

Step 2: To a mixed solution of compound 3a (52 g, 0.227 mol) in EtOH (200 ml) and H ₂ O (180 ml) was added KOH (228 g, 4.09 mol), the above reaction mixture was stirred at 90°C overnight, TLC showed the compound After 3a was completely consumed, the reaction mixture was cooled to room temperature, most of the ethanol was evaporated, the pH of the system was adjusted to 4-5 with 2N hydrochloric acid, a solid was precipitated, filtered and collected, and the solid was rotary evaporated with toluene 5 times to remove water. , the crude product 4a (57 g, 100%) was obtained, which was used in the next step without purification. ¹ H NMR (DMSO-d6, 400MHz): δ=7.88(d,1H), 7.50-7.46(m,2H), 7.29-7.27(m,1H), 7.17-7.15(m,2H), 7.08(d ,1H),6.98-6.95(m,1H).

Step 3: Under nitrogen protection, a solution of compound 4a (57 g, 0.257 mol) and K ₂ CO ₃ (106 g, 0.771 mol) in DMF (360 ml) was cooled to 0 °C, and iodomethane (40 g, 0.283mol), after the dropwise addition, the above reaction mixture was raised to room temperature and the reaction was continued to stir for 4-6h until TLC monitoring showed that compound 4a was completely consumed, water was added to the reaction mixture and extracted with ethyl acetate (200ml x 3). The organic phase was washed with water and brine, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain the crude product. The mixed solvent of PE and EA was used as the elution solvent, and purified by flash chromatography to obtain an oily substance 5a (40 g, yield 67 %). ¹ H NMR (DMSO-d6, 400MHz): δ=7.88(d,1H), 7.50-7.46(m,2H), 7.30-7.28(m,1H), 7.17-7.15(m,2H), 7.11(d) ,1H),6.99-6.97(m,1H),3.84(s,3H).

Step 4: Under argon protection, a solution of compound 6 (4.0 g, 17.3 mmol) in THF (50 mL) was cooled to -78 °C, and n-butyllithium (1.6 M in hexane, 23 mL) was added dropwise to the mixed solution. , 36.3 mmol), this mixed solution was continued to stir at -78 °C for 1 hour, and then a solution of compound 5a (4.8 g, 18.1 mmol) in THF (15 ml) pre-cooled to -78 °C was added. The reaction mixture was stirred at -78°C for 3-5 hours until TLC monitoring showed complete consumption of compound 6, then quenched with 1 N HCl. The reaction mixture was warmed to room temperature, extracted with EA, washed with saturated brine, the organic phase was dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain a crude product, which was recrystallized from ethyl acetate to obtain compound 7a (2.9 g, yield: 43%). ¹ H NMR (DMSO-d6, 400MHz): δ=12.96(s, 1H), 8.31(d, 1H), 7.97(s, 1H), 7.56(d, 1H), 7.50-7.46(m, 2H), 7.38-7.37(m,1H),7.27-7.24(m,1H),7.19-7.15(m,3H),7.02-7.00(m,1H).

The fifth step: under nitrogen protection, the THF (35 mL) solution of compound 7a (2.8 g, 7.3 mmol) was cooled to 0 °C, and NaH (0.35 g, 8.7 mmol, 60% in oil) was added to this solution in batches, After the addition was completed, the mixture was continued to stir for 30 min, then SEMCl (1.8 g, 10.9 mmol) was added dropwise, the reaction mixture was warmed to room temperature and stirred for 3-5 hours, TLC monitored the reaction compound 7a was completely consumed, at 0 ° C with The reaction was quenched with saturated NH ₄ Cl, extracted with ethyl acetate (20 ml x 3), washed with water and saturated brine, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain crude product, silica gel column Chromatographic purification gave compound 8a (2.1 g, yield: 57%). ¹ H NMR (DMSO-d6, 400MHz): δ=8.38(d,1H), 8.20(s,1H), 7.49(d,1H), 7.46-7.44(m,3H), 7.28-7.24(m,1H) ),7.18-7.15(m,3H),7.02-7.00(m,1H),5.67(s,2H),3.55-3.51(m,2H),0.81-0.77(m,2H),0.12(s,9H) ).

Table 1. Intermediates and analytical data

Similarly, intermediates 8o-8q (Table 1) were prepared according to Scheme 2 and Scheme 3 according to known literature methods: 8o-8q (WO2004056830), 8r-8t (MonatshChem 148305 314 2017).

Scenario 2:

Scenario 3:

Scenario 4:

Compound 8 (0.39 mmol) and compound 21 (0.59 mmol), Pd(OAc) ₂ (18 mg, 0.078 mmol) or Pd ₂ (dba) ₃ (71 mg, 0.078 mmol), Cs ₂ CO ₃ (509 mg, 1.56 mmol) _A mixture of ^tBu3PHBF4 ( ₂₃ mg, 0.078 mmol) in THF (5 mL) or Tol (5 mL) was stirred at 100-120 °C for 4-8 h until TLC showed complete consumption of compound 8, then the reaction mixture was cooled to At room temperature, extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and brine, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain the crude product, which was a mixture of PE and EA on a silica gel column. Purification by flash chromatography to elute solvent gave product 22 in moderate to good yields.

Scenario 5:

To a solution of compound 22 (80 mg) in DCM (1 ml) was added TFA (0.5 ml), the reaction mixture was stirred at room temperature for 3-8 hours, until TLC monitoring of the reaction showed complete consumption of compound 22, the solvent was evaporated and saturated with The pH was adjusted to 7 with NaHCO ₃ , extracted with ethyl acetate (8 mL×3), the organic phase was washed with water and brine, respectively, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to obtain the crude product, which was purified by preparative TLC , the product was obtained in moderate to good yields.

Example 1: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Hexane-1-carboxylate methyl ester (I-1)

Compounds were prepared according to general scheme 4 using intermediates 8a (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 504.2 (M+H) ⁺ .

Example 2: (1s,4s)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Hexane-1-carboxylate methyl ester (I-2)

Compounds were prepared following general scheme 4 using intermediates 8a (Table 1) and (1s,4s)-4-aminocyclohexane-1-carboxylate methyl ester (21b) to give the desired product.

MS m/z: 504.2 (M+H) ⁺ .

Example 3: (1s,3s)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Butane-1-carboxylate methyl ester (I-3)

Compounds were prepared according to general scheme 4 using intermediates 8a (Table 1) and (1s,3s)-3-aminocyclobutane-1-carboxylic acid methyl ester (21c) to give the desired product.

MS m/z: 476.1 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.70 (d, 1H), 7.93 (d, 1H), 7.56-7.54 (m, 2H), 7.49 -7.45(m, 2H), 7.27-7.23(m, 1H), 7.19-7.17(m, 3H), 7.03-7.01(m, 1H), 6.23(d, 1H), 4.06-4.04(m, 1H) , 3.62(s, 3H), 3.01-2.98(m, 1H), 2.78-2.76(m, 2H), 2.11-2.08(m, 2H).

Example 4: (1r,3r)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Butane-1-carboxylate methyl ester (I-4)

Compounds were prepared according to general scheme 4 using intermediates 8a (Table 1) and (1r,3r)-3-aminocyclobutane-1-carboxylic acid methyl ester (21d) to give the desired product.

MS m/z: 476.1 (M+H) ⁺ .

Scenario 6:

To a mixed solution of compound 22a (100 mg, 0.158 mmol) in EtOH (2 ml) and H2O (0.5 ml) was added LiOH (7.6 mg, 0.316 mmol). The reaction mixture was stirred at 60-80 °C for 1-3 h, until TLC monitoring of the reaction showed that compound 22a was completely consumed, then the reaction mixture was cooled to room temperature, most of the solvent was evaporated, and the pH of the system was adjusted to about 5 with 1N HCl, Extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and brine, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain the crude product, which was purified by preparative TLC to obtain the product in moderate to good yield.

Example 5: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexane-1-carboxylic acid (I-5)

MS m/z: 490.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.74 (d, 1H), 8.02 (d, 1H), 7.65-7.55 (m, 4H), 7.37 -7.29(m,1H),7.29-7.26(m,3H),7.12-7.10(m,1H),6.48(d,1H),2.61-2.45(m,1H),2.24-2.20(m,2H) , 2.10-2.06 (m, 3H), 1.66-1.63 (m, 2H), 1.45-1.42 (m, 2H); 13C NMR (DMSO, 400MHz): δ=189.7, 176.9, 158.8, 155.8, 150.3, 149.2, 145.9, 137.9, 134.6, 131.6, 131.1, 130.8, 125.1, 120.1, 119.5, 117.6, 116.7, 105.7, 98.8, 55.4, 50.1, 41.9, 31.7, 27.7.

Example 6: (1s,4s)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexane-1-carboxylic acid (I-6)

MS m/z: 490.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.87 (d, 1H), 7.93 (d, 1H), 7.57-7.54 (m, 2H), 7.49 -7.45(m,2H),7.26-7.23(m,1H),7.19-7.17(m,3H),7.03-7.01(m,1H),6.38(d,1H),3.78-3.73(m,1H) , 2.47-2.43 (m, 1H), 1.89-1.72 (m, 8H).

Example 7: (1r,4r)-4-((3-(4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexane- 1-Carboxylic acid (I-7)

Compounds were prepared following general scheme 4 using intermediates 8b (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 456.2 (M+H) ⁺ .

Example 8: (1s,4s)-4-((3-(4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexane- 1-Carboxylic acid (I-8)

This compound was prepared according to general scheme 4, using intermediate 8b (Table 1) and (1s,4s)-4-aminocyclohexane-1-carboxylate methyl ester (21b) to give the desired product.

MS m/z: 456.6 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.91 (d, 1H), 7.89 (d, 1H), 7.75 (d, 2H), 7.69 (s ,1H),7.43-7.39(m,2H),7.20-7.19(m,1H),7.10(d,2H),7.02(d,2H),6.34(d,1H),3.73-3.71(m,1H) ), 2.44-2.38(m, 1H), 1.82-1.76(m, 4H), 1.74-1.66(m, 4H).

Example 9: (1S,3R)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclopentane-1-carboxylic acid (I-9)

Compounds were prepared according to general scheme 4 using intermediates 8a (Table 1) and (1S,3R)-3-aminocyclopentane-1-carboxylic acid methyl ester (21e) to give the desired product.

MS m/z: 476.1 (M+H) ⁺ .

Example 10: (1R,3S)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclopentane-1-carboxylic acid (I-10)

Compounds were prepared following general scheme 4 using intermediates 8a (Table 1) and (1R,3S)-3-aminocyclopentane-1-carboxylate methyl ester (21f) to give the desired product.

MS m/z: 476.1 (M+H) ⁺ .

Example 11: (1s,3s)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclobutane-1-carboxylic acid (I-11)

MS m/z: 462.4 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.70 (d, 1H), 7.94 (d, 1H), 7.56-7.54 (m, 2H), 7.49 -7.45(m, 2H), 7.27-7.23(m, 1H), 7.19-7.17(m, 3H), 7.03-7.01(m, 1H), 6.23(d, 1H), 4.03-4.00(m, 1H) , 2.92-2.88 (m, 1H), 2.75-2.73 (m, 2H), 2.08-2.06 (m, 2H).

Example 12: (1r,3r)-3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclobutane-1-carboxylic acid (I-12)

MS m/z: 462.1 (M+H) ⁺ .

Example 13: (1r,4r)-4-((3-(2-Chloro-4-(pyridin-3-oxy)benzoyl)-1H-pyrro[2,3-b]pyridine-4- base)amino)cyclohexane-1-carboxylic acid (I-13)

Compounds were prepared according to general scheme 4 using intermediates 8c (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 491.1 (M+H) ⁺ .

Example 14: (1s,4s)-4-((3-(2-Chloro-4-(pyridin-4-oxy)benzoyl)-1H-pyrro[2,3-b]pyridine-4- base)amino)cyclohexane-1-carboxylic acid (I-14)

Following general scheme 4, this compound was prepared using intermediate 8d (Table 1) and (1s,4s)-4-aminocyclohexane-1-carboxylic acid methyl ester (21b) to give the desired product.

MS m/z: 491.1 (M+H) ⁺ .

Example 15: (1r,4r)-4-((3-(3-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexane-1-carboxylic acid (I-15)

Compounds were prepared according to general scheme 4 using intermediates 8e (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 490.2 (M+H) ⁺ .

Example 16: (1r,4r)-4-((3-(4-phenoxy-2-(trifluoromethyl)benzoyl)-1H-pyrro[2,3-b]pyridine-4- base)amino)cyclohexane-1-carboxylic acid (I-16)

Compounds were prepared following general scheme 4 using intermediates 8f (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylate methyl ester (21a) to give the desired product.

MS m/z: 524.2 (M+H) ⁺ .

Example 17: (1s,4s)-4-((3-(4-phenoxy-2-(trifluoromethyl)benzoyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)cyclohexane-1-carboxylic acid (I-17)

Compounds were prepared following general scheme 4 using intermediates 8f (Table 1) and (1s,4s)-4-aminocyclohexane-1-carboxylic acid methyl ester (21b) to give the desired products.

MS m/z: 524.2 (M+H) ⁺ .

Example 18: (1r,4r)-4-((3-(2-methyl-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino ) cyclohexane-1-carboxylic acid (I-18)

Compounds were prepared according to general scheme 4, using intermediate 8g (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 470.2 (M+H) ⁺ .

Example 19: (2-Chloro-4-phenoxyphenyl)(4-(cyclopentylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-19 )

The compound was prepared according to general scheme 4 using intermediate 8a (Table 1) and cyclopentylamine (21 g) to give the desired product.

MS m/z: 432.1 (M+H) ⁺ .

Example 20: (2-Chloro-4-phenoxyphenyl)(4-(cyclohexylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-20 )

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and cyclohexylamine (21h) to give the desired product.

MS m/z: 446.2 (M+H) ⁺ .

Example 21: (2-Chloro-4-phenoxyphenyl)(4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrro[2,3-b]pyridine-3 -yl) ketone (I-21)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and tetrahydro-2H-pyran-4-amine (21i) to give the desired product.

MS m/z: 448.1 (M+H) ⁺ .

Example 22: (2-Chloro-4-phenoxyphenyl)(4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone ( I-22)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and tert-butyl 4-aminopiperidine-1-carboxylate (21j) to give the desired product.

MS m/z: 447.2(M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400MHz): δ=8.75(d,1H), 8.06(d,1H), 7.66(s,1H), 7.60-7.56 (m,3H),7.37-7.33(m,1H),7.29-7.26(m,3H),7.14-7.11(m,1H),6.53(d,1H),3.96-3.94(m,1H),3.46 -3.42(m, 2H), 3.24-3.19(m, 2H), 2.34-2.30(m, 2H), 1.85-1.80(m, 2H).

Example 23: (R)-(2-Chloro-4-phenoxyphenyl)(4-(piperidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl ) ketone (I-23)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (21k) to give the desired product

MS m/z: 447.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=9.00 (s, 1H), 8.60 (d, 1H), 7.99 (d, 1H), 7.54-7.46 (m, 4H), 7.27-7.23 (m, 1H), 7.19-7.17 (m, 3H), 7.04-7.01 (m, 1H), 6.46 (d, 1H), 3.96-3.94 (m, 1H), 3.27 -3.24(m, 2H), 2.97-2.92(m, 1H), 2.86-2.81(m, 1H), 2.16-2.13(m, 1H), 1.98-1.95(m, 1H), 1.87-1.83(m, 1H), 1.72-1.67 (m, 1H).

Example 24: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-hydroxycyclohexyl)amino)-1H-pyrro[2,3-b]pyridine-3 -yl) ketone (I-24)

Compounds were prepared following general scheme 4 using intermediates 8a (Table 1) and (1r,4r)-4-aminocyclohexane-1-ol (211) to give the desired product.

MS m/z: 462.2(M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400MHz): δ=8.52(d,1H), 7.90(d,1H), 7.53(d,1H), 7.50-7.46 (m,4H),7.27-7.23(m,1H),7.19-7.16(m,3H),7.03-7.00(m,1H),6.33(d,1H),4.61-4.60(m,1H),3.54 -3.53 (m, 1H), 2.09-2.06 (m, 2H), 1.90-1.87 (m, 2H), 1.39-1.32 (m, 4H).

Example 25: (2-Chloro-4-phenoxyphenyl)(4-(((1s,4s)-4-hydroxycyclohexyl)amino)-1H-pyrro[2,3-b]pyridine-3 -yl) ketone (I-25)

Compounds were prepared following general scheme 4 using intermediates 8a (Table 1) and (1s,4s)-4-aminocyclohexane-1-ol (21m) to give the desired product.

MS m/z: 462.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=7.77 (d, 1H), 7.44-7.40 (m, 3H), 7.24-7.20 (m, 2H) ,7.13-7.11(m,2H),6.78-6.77(m,1H),6.63-6.61(m,1H),6.34(d,1H),5.61-5.59(m,1H),5.13-5.10(m, 1H), 3.66-3.63 (m, 1H), 1.86-1.84 (m, 4H), 1.56-1.54 (m, 4H).

Example 26: (2-Chloro-4-phenoxyphenyl)(4-((6-hydroxyspiro[3.3]heptan-2-yl)amino)-1H-pyrrole[2,3-b] Pyridin-3-yl)methanone (I-26)

Compounds were prepared according to general scheme 4 using intermediate 8a (Table 1) and 6-aminospiro[3.3]heptan-2-ol (21n) to give the desired product.

MS m/z: 474.2 (M+H) ⁺ .

Example 27: (2-Chloro-4-phenoxyphenyl)(4-((2-(2-ethoxyethoxy)ethyl)amino)-1H-pyrrolo[2,3-b ]pyridin-3-yl)methanone (I-27)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and 2-(2-ethoxyethoxy)ethane-1-amine (21o) to give the desired product

MS m/z: 480.2 (M+H) ⁺ .

Example 28: (2-Chloro-4-phenoxyphenyl)(4-((2-(2-hydroxyethoxy)ethyl)amino)-1H-pyrrolo[2,3-b]pyridine- 3-yl)methanone (I-28)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and 2-(2-aminoethoxy)ethane-1-ol (21p) to give the desired product.

MS m/z: 452.1 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.65-8.63 (m, 1H), 7.94 (d, 1H), 7.54-7.45 (m, 4H) ,7.28-7.24(m,1H),7.19-7.17(m,3H),7.03-7.01(m,1H),6.33(d,1H),4.57-4.54(m,1H),3.72-3.70(m, 2H), 3.55-3.51 (m, 4H), 3.45-3.41 (m, 2H).

Example 29: (2-Chloro-4-phenoxyphenyl)(4-((2-hydroxyethyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-29)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and 2-aminoethane-1-ol (21q) to give the desired product.

MS m/z: 408.1 (M+H) ⁺ .

Example 30: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrole[2,3-b ]pyridin-3-yl)methanone (I-30)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 476.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=9.08 (d, 1H), 7.98 (d, 1H), 7.61 (s, 1H), 7.57 (d ,1H),7.51-7.47(m,2H),7.28-7.25(m,1H),7.20-7.18(m,3H),7.05-7.02(m,1H),6.53(d,1H),4.45-4.43 (m,1H),3.33-3.28(m,2H),2.15-2.13(m,2H),1.85-1.82(m,2H),1.45-1.43(m,1H),1.33-1.30(m,2H) , 1.18-1.14 (m, 2H).

Example 31: (2-Chloro-4-phenoxyphenyl)(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrole[2,3-b ]pyridin-3-yl)methanone (I-31)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired product.

MS m/z: 477.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.88 (d, 1H), 7.92 (d, 1H), 7.57-7.53 (m, 2H), 7.48 -7.46(m,2H),7.31-7.26(m,1H),7.19-7.17(m,3H),7.04-7.02(m,1H),6.84(d,1H),4.46-4.45(m,1H) ,3.88-3.87(m,1H),3.29-3.27(m,2H),1.80-1.76(m,2H),1.65-1.63(m,2H),1.55-1.52(m,2H),1.38-1.32( m, 2H).

Example 32: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 1H-pyrrole[2,3-b]pyridin-3-yl)methanone (I-32)

Compounds were prepared following general scheme 4 using intermediates 8a (Table 1) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (21t) to give the desired product.

MS m/z: 478.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.46 (d, 1H), 7.93 (d, 1H), 7.55-7.53 (m, 2H), 7.50 -7.46(m,2H),7.27-7.23(m,1H),7.20-7.17(m,3H),7.03-7.00(m,1H),6.42(d,1H),4.70(s,1H),4.13 -4.10(m, 1H), 3.61-3.57(m, 1H), 3.38-3.37(m, 1H), 3.15-3.10(m, 2H), 2.25-2.21(m, 1H), 1.80-1.76(m, 1H), 1.55-1.52 (m, 1H), 1.23-1.15 (m, 1H), 1.18-1.14 (m, 2H).

Example 33: (4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-phenoxy) Phenyl) ketone (I-33)

Compounds were prepared following general scheme 4 using intermediate 8b (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired product.

MS m/z: 442.2 (M+H) ⁺ .

Scenario 7:

To a mixed solution of compound 23a (150 mg, 0.24 mmol) in THF (3 ml) was added three drops of DMF and the reaction mixture was cooled to 0°C, then oxalyl chloride (34 mg, 0.27 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 1-2 hours until TLC monitoring of the reaction showed complete consumption of compound 23a, the solvent was evaporated, the residue was dissolved in THF and added to 24a-c (0.73 mmol) in THF (3 ml), respectively ) solution, the reaction mixture was further stirred for 0.5-1 h, extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and brine respectively, and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to obtain the crude product. Products 25a-c were purified by preparative thin layer chromatography in moderate to good yields.

Example 34: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexane-1-carboxamide (I-34)

This compound was prepared according to general scheme 7 using intermediate 23a and ammonia (24a) to give the desired product.

MS m/z: 489.2 (M+H) ⁺ .

Example 35: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrro[2,3-b]pyridin-4-yl)amino)- N-methylcyclohexane-1-carboxamide (I-35)

This compound was prepared according to general scheme 7 using intermediate 23a and methylamine (24b) to give the desired product.

MS m/z: 503.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.66 (d, 1H), 7.93 (d, 1H), 7.73-7.71 (m, 1H), 7.55 -7.52(m,2H),7.49-7.46(m,2H),7.27-7.23(m,1H),7.19-7.17(m,3H),7.03-7.00(m,1H),6.41(d,1H) ,3.49-3.46(m,1H),2.58(d,3H),2.20-2.14(m,3H),1.83-1.80(m,2H),1.63-1.53(m,2H),1.33-1.22(m, 2H); 13C NMR (DMSO, 400MHz): δ=189.8, 175.6, 158.8, 155.8, 150.3, 149.3, 134.6, 131.6, 131.1, 130.8, 125.1, 120.1, 119.5, 117.6, 116.7, 105.8, 98.8, 55.4 , 43.6, 32.1, 28.4, 25.9.

Example 36: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) -N-(Methylsulfonyl)cyclohexane-1-carboxamide (I-36)

This compound was prepared according to general scheme 7 using intermediate 23a and methylsulfonamide (24c) to provide the desired product.

MS m/z: 567.1 (M+H) ⁺ .

Scenario 8:

Step 1: To a solution of compound 22j (200 mg) in DCM (5 ml) was added TFA (0.5 ml). The reaction mixture was stirred at room temperature for 0.5-1 h until TLC monitoring of the reaction showed that compound 22j was completely consumed, most of the solvent was evaporated, the pH was adjusted to 7 with saturated NaHCO ₃ , extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and The organic phases were washed with brine and combined, dried _over anhydrous _Na2SO4 and evaporated to dryness to give the crude compound, which was purified by preparative TLC to give the product in moderate to good yields.

Step 2: To a mixed solution of compound 26 (100 mg, 0.17 mmol) in DCM (3 ml) was added DIPEA (67 mg, 0.52 mmol). The reaction mixture was cooled to 0°C, then compound 27a (30 mg, 0.26 mmol) was added in portions, the reaction mixture was stirred at 0°C to room temperature for 1-2 hours, until TLC monitoring of the reaction showed that compound 26 was completely consumed, evaporated. Most of the solvent was extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and brine and the organic layers were combined, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to obtain crude product. Purification by preparative thin layer chromatography gave the product 28 (80 mg, 70% yield).

Example 37: 4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)piperidine-1-sulfone Amide (I-37)

This compound was prepared according to general scheme 8 using intermediate 22j and sulfamoyl chloride (27a) to give the desired product.

MS m/z: 526.1 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.62 (d, 1H), 7.94 (d, 1H), 7.55-7.53 (m, 2H), 7.50 -7.46(m,2H),7.27-7.23(m,1H),7.19-7.17(m,3H),7.03-7.01(m,1H),6.82(s,2H),6.41(d,1H),3.65 -3.63 (m, 1H), 3.47-3.44 (m, 2H), 2.90-2.85 (m, 2H), 2.14-2.12 (m, 2H), 1.63-1.54 (m, 2H).

Example 38: (2-Chloro-4-phenoxyphenyl)(4-((1-(methylsulfonyl)piperidin-4-yl)amino)-1H-pyrrolo[2,3-b] Pyridin-3-yl)methanone (I-38)

This compound was prepared according to general scheme 8 using intermediate 22j and methanesulfonyl chloride (27b) to provide the desired product.

MS m/z: 525.1 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.69 (d, 1H), 7.95 (d, 1H), 7.56-7.54 (m, 2H), 7.50 -7.46(m,2H),7.27-7.23(m,1H),7.20-7.18(m,3H),7.05-7.01(m,1H),6.41(d,1H),3.75-3.73(m,1H) , 3.54-3.52(m, 2H), 3.10-3.05(m, 2H), 2.91(s, 3H), 2.14-2.11(m, 2H), 1.64-1.59(m, 2H).

Example 39: 3-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclopentane-1- Sulfonamide (I-39)

This compound was prepared according to general scheme 8 using intermediate 22u and sulfamoyl chloride (27a) to give the desired product.

MS m/z: 511.1 (M+H) ⁺ .

Scenario 9:

Step 1: To a mixed solution of compound 7a (0.5 g, 1.31 mmol) in EtOH (15 mL) under _N2 protection, NaBH4 ₍ 498 mg, 13.1 mmol) was added portionwise, and the reaction mixture was stirred at room temperature overnight until TLC monitoring The reaction showed that compound 7a was completely consumed, the reaction solution was quenched with saturated NH ₄ Cl, extracted with ethyl acetate (20 mL×3), the organic phases were washed with water and brine respectively and the organic phases were combined, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain crude Product 29 (500 mg, yield: 100%). It was used in the next synthesis without further purification.

Step 2: To a mixed solution of compound 29 (500 mg, 1.30 mmol) in DCM (8 ml) was added TFA (594 mg, 5.21 mmol) and _Et3SiH (606 mg, 5.21 mmol) and the reaction mixture was stirred at room temperature until TLC monitoring The reaction showed that compound 29 was completely consumed, most of the solvent was evaporated, the organic phase was adjusted to pH 7 with saturated NaHCO ₃ , extracted with ethyl acetate (15 mL×3), the organic phase was washed with water and brine, respectively, dried over anhydrous Na ₂ SO ₄ and Evaporated to dryness to obtain the crude product, which was purified by silica gel column to obtain compound 30 (300 mg, yield: 63%).

Step 3: Under the protection of _N2 , the solution of compound 30 (300 mg, 0.815 mmol) in THF (8 mL) was cooled to about 0 °C, NaH (49 mg, 1.22 mmol, 60% inoil) was added to the above solution in batches, Then the reaction mixture was stirred for 30 min, and then SEMCl (203 mg, 1.22 mmol) was added dropwise. After the addition was completed, it was stirred at room temperature for 1-3 h. TLC monitored the reaction compound 30 was completely consumed, and quenched with saturated NH ₄ Cl at 0 °C. The reaction was extracted with ethyl acetate (10 ml×3), the combined organic layers were washed with water and brine, dried over anhydrous Na ₂ SO ₄ and evaporated to dryness to obtain the crude product, which was purified by silica gel column to obtain compound 31 (360 mg, yield: 89%).

Example 40: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Hexane-1-carboxylic acid (I-40)

Compounds were prepared following general scheme 9 using intermediate 31 and (1r,4r)-4-aminocyclohexane-1-carboxylate methyl ester (21a) to give the desired product.

MS m/z: 476.5 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=11.41 (s, 1H), 7.87 (d, 1H), 7.43-7.39 (m, 2H), 7.20 -7.16(m,2H),7.05-7.01(m,3H),6.94-6.92(m,1H),6.90(s,1H),6.34(d,1H),4.91-4.89(m,1H),4.25 (s, 2H), 2.13-2.07 (m, 1H), 1.89-1.85 (m, 4H), 1.50-1.42 (m, 2H), 1.06-1.01 (m, 2H).

Example 41: (1s,4s)-4-((3-(2-Chloro-4-phenoxybenzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) ring Hexane-1-carboxylic acid (I-41)

This compound was prepared according to general scheme 9 using intermediate 31 and (1s,4s)-4-aminocyclohexane-1-carboxylic acid methyl ester (21b) to give the desired product.

MS m/z: 476.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=11.61 (s, 1H), 7.89 (d, 1H), 7.42-7.38 (m, 2H), 7.19 -7.15(m,1H),7.14-7.13(m,1H),7.04-7.02(m,2H),6.99-6.96(m,1H),6.91(s,1H),6.88-6.85(m,1H) ,6.37(d,1H),5.24-5.22(m,1H),4.26(s,2H),3.59-3.57(m,1H),2.42-2.41(m,1H),1.64-1.60(m,6H) , 1.45-1.41 (m, 2H).

Example 42: ((1s,4s)-4-((3-(2-Chloro-4-phenoxybenzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexyl) methanol (I-42)

This compound was prepared according to general scheme 9 using intermediate 33 and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired product.

MS m/z: 462.2 (M+H) ⁺ .

Example 43: ((1r,4r)-4-((3-(2-Chloro-4-phenoxybenzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) Cyclohexyl) methanol (I-43)

This compound was prepared according to general scheme 9 using intermediate 33 and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 462.2 (M+H) ⁺ .

Example 44: ((1s,4s)-4-((3-(4-phenoxybenzyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)cyclohexyl)methanol (I-44)

This compound was prepared according to general scheme 9 using intermediate 33 and (1s,4s)-4-aminocyclohexane-1-carboxylic acid methyl ester (21b) to give the desired product.

MS m/z: 428.2 (M+H) ⁺ .

Example 45: (4((4(hydroxymethyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(4-phenoxyphenyl)methanone (I -45)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and p-aminobenzyl alcohol (21z) to give the desired product.

MS m/z: 436.2 (M+H) ⁺ .

Example 46: (1r,4r)-4-((3-(2-Chloro-4-(pyridin-3-oxy)benzoyl)-1H-pyrrolo[2,3-b]pyridine-4 -yl)amino)cyclohexane-1-carboxylic acid (I-46)

MS m/z: 491.1 (M+H) ⁺ .

Example 47: (1s,4s)-4-((3-(2-chloro-4-(pyridin-3-oxy)benzoyl)-1H-pyrro[2,3-b]pyridine-4- base)amino)cyclohexane-1-carboxylic acid (I-47)

This compound was prepared according to general scheme 4 using intermediate 8c (Table 1) and (1s,4s)-4-aminocyclohexane-1-carboxylic acid methyl ester (21b) to give the desired product.

MS m/z: 491.1 (M+H) ⁺ .

Example 48: (1s,4s)-4-((3-(2-Chloro-4-(pyridin-4-oxy)benzoyl)-1H-pyrro[2,3-b]pyridine-4- base)amino)cyclohexane-1-carboxylic acid (I-48)

MS m/z: 491.1 (M+H) ⁺ .

Example 49: (2-Chloro-4-(pyridin-3-oxy)phenyl)(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[ 2,3-b]pyridin-3-yl)methanone (I-49)

Compounds were prepared following general scheme 4 using intermediates 8c (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 477.2 (M+H) ⁺ .

Example 50: (2-Chloro-4-(pyridin-3-oxy)phenyl)(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo [2,3-b]pyridin-3-yl)methanone (I-50)

Compounds were prepared following general scheme 4 using intermediate 8c (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired product.

MS m/z: 477.2 (M+H) ⁺ .

Example 51: (2-Chloro-4-(pyridin-4-oxy)phenyl)(4-((1s,4s)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[ 2,3-b]pyridin-3-yl)methanone (I-51)

Compounds were prepared following general scheme 4 using intermediates 8d (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired products.

MS m/z: 477.2 (M+H) ⁺ .

Example 52: (2-Chloro-4-((5-methoxypyridin-3-yl)oxy)phenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl )amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-52)

Compounds were prepared following general scheme 4 using intermediates 8h (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 507.2 (M+H) ⁺ .

Example 53: (2-Chloro-4-((2-methoxypyridin-4-yl)oxy)phenyl)(4-(((1s,4s)-4)-(hydroxymethyl)ring Hexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-53)

Compounds were prepared following general scheme 4 using intermediate 8i (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired product.

MS m/z: 507.2 (M+H) ⁺ .

Example 54: (2-Chloro-4-((5-methylpyridin-3-yl)oxy)phenyl)(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino )-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-54)

Compounds were prepared according to general scheme 4 using intermediates 8j (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired products.

MS m/z: 491.2 (M+H) ⁺ .

Example 55: (2-Chloro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)(4-(((1r,4r)-4-(hydroxymethyl) )cyclohexyl)amino)-1H-pyrro[2,3-b]pyridin-3-yl)methanone (I-55)

Compounds were prepared following general scheme 4 using intermediates 8k (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 545.2 (M+H) ⁺ .

Example 56: (2-Chloro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)(4-((1s,4s)-4-(hydroxymethyl) Cyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)methanone (I-56)

Compounds were prepared following general scheme 4 using intermediates 8k (Table 1) and ((1s,4s)-4-aminocyclohexyl)methanol (21s) to give the desired products.

MS m/z: 545.2 (M+H) ⁺ .

Example 57: (2-Chloro-4-(pyrimidin-5-oxy)phenyl)(4-((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrrolo[ 2,3-b]pyridin-3-yl)methanone (I-57)

Compounds were prepared according to general scheme 4 using intermediate 81 (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 478.2 (M+H) ⁺ .

Example 58: N-(3-Chloro-4-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrro[2,3-b]pyridine-3 -Carbonyl)phenyl)-2-methoxybenzamide (I-58)

Compounds were prepared following general scheme 4 using intermediates 8o (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 533.2 (M+H) ⁺ .

Example 59: N-(3-Chloro-4-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrro[2,3-b]pyridine-3 -Carbonyl)phenyl)-5-fluoro-2-methoxybenzamide (I-59)

Compounds were prepared following general scheme 4 using intermediates 8p (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired products.

MS m/z: 551.2 (M+H) ⁺ .

Example 60: N-(3-Chloro-4-(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrro[2,3-b]pyridine-3 -Carbonyl)benzyl)-5-fluoro-2-methoxybenzamide (I-60)

Compounds were prepared following general scheme 4 using intermediates 8q (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 565.2 (M+H) ⁺ .

Scenario 10:

Example 61: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)amino) -N-(2-hydroxyethyl)cyclohexane-1-carboxamide (I-61)

Compounds were prepared according to general scheme 10 using compound 1-5 and 2-aminoethane-1-ol to give the desired product.

MS m/z: 533.2 (M+H) ⁺ .

Example 62: (1r,4r)-4-((3-(2-Chloro-4-(2-methoxyphenoxy)benzoyl)-1H-pyrro[2,3-b]pyridine- 4-yl)amino)cyclohexane-1-carboxylic acid (I-62)

Compounds were prepared according to general scheme 4 using intermediates 8m (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 520.2 (M+H) ⁺ .

Example 63: (1r,4r)-4-((3-(2-Chloro-4-(5-fluoro-2-methoxyphenoxy)benzoyl)-1H-pyrro[2,3- b]Pyridin-4-yl)amino)cyclohexane-1-carboxylic acid (I-63)

Compounds were prepared following general scheme 4 using intermediates 8n (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylic acid methyl ester (21a) to give the desired product.

MS m/z: 538.2 (M+H) ⁺ .

Example 64: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1Hpyrazolo[3,4-b]pyridin-4-yl)amino) Cyclohexane-1-carboxylic acid (I-64)

Compounds were prepared following general scheme 4 using intermediates 8r (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylate methyl ester (21a) to give the desired product

MS m/z: 491.1 (M+H) ⁺ .

Example 65: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrazolo[3,4 -b]pyridin-3-yl)methanone (I-65)

Compounds were prepared following general scheme 4 using intermediates 8r (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 477.2 (M+H) ⁺ .

Example 66: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 1H-pyrazolo[3,4-b]pyridin-3-yl)methanone (I-66)

Compounds were prepared following general scheme 4 using intermediates 8r (Table 1) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (21t) to give the desired product.

MS m/z: 479.1 (M+H) ⁺ .

Example 67: (1r,4r)-4-((5-(2-Chloro-4-phenoxybenzoyl)-7H-pyrrolo[2,3-c]pyridazin-4-yl)amino ) cyclohexane-1-carboxylic acid (I-67)

Compounds were prepared following general scheme 4 using intermediates 8s (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylate methyl ester (21a) to give the desired product.

MS m/z: 491.1 (M+H) ⁺ .

Example 68: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-7H-pyrrolo[2,3- c]pyridazin-5-yl)methanone (I-68)

MS m/z: 477.2 (M+H) ⁺ .

Example 69: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 7H-pyrrolo[2,3-c]pyridazin-5-yl)methanone (I-69)

Compounds were prepared following general scheme 4 using intermediates 8s (Table 1) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (21t) to give the desired product.

MS m/z: 479.1 (M+H) ⁺ .

Example 70: (1r,4r)-4-((3-(2-Chloro-4-phenoxybenzoyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino ) cyclohexane-1-carboxylic acid (I-70)

Compounds were prepared following general scheme 4 using intermediates 8t (Table 1) and (1r,4r)-4-aminocyclohexane-1-carboxylate methyl ester (21a) to give the desired product.

MS m/z: 492.1 (M+H) ⁺ .

Example 71: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)amino)-1H-pyrazolo[3,4- d]pyrimidin-3-yl)methanone (I-71)

Compounds were prepared following general scheme 4 using intermediates 8t (Table 1) and ((1r,4r)-4-aminocyclohexyl)methanol (21r) to give the desired product.

MS m/z: 478.2 (M+H) ⁺ .

Example 72: (2-Chloro-4-phenoxyphenyl)(4-(((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)amino)- 1H-pyrazolo[3,4-d]pyrimidin-3-yl)methanone (I-72)

Compounds were prepared following general scheme 4 using intermediates 8t (Table 1) and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol (21t) to give the desired product.

MS m/z: 480.1 (M+H) ⁺ .

Example 73: (4-(((1r,4r)-4-aminocyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy Phenyl) ketone (I-73)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate (21v) to give the desired product.

MS m/z: 461.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.68 (s, 1H), 8.04 (s, 2H), 7.94 (d, 1H), 7.55-7.53 (m,2H),7.50-7.46(m,2H),7.27-7.24(m,1H),7.20-7.18(m,3H),7.03-7.00(m,1H),6.45(d,1H),3.49 -3.45(m, 1H), 3.13-3.11(m, 1H), 2.18-2.15(m, 2H), 2.04-2.01(m, 2H), 1.56-1.53(m, 2H), 1.45-1.42(m, 2H).

Example 74: (4-(((1s,4s)-4-aminocyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy phenyl) ketone (I-74)

This compound was prepared according to general scheme 4 using intermediate 8a (Table 1) and tert-butyl ((1s,4s)-4-aminocyclohexyl)carbamate (21w) to give the desired product.

MS m/z: 461.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.72 (s, 1H), 8.00 (s, 2H), 7.93 (d, 1H), 7.56-7.54 (m,2H),7.50-7.46(m,2H),7.27-7.24(m,1H),7.19-7.17(m,3H),7.04-7.01(m,1H),6.32(d,1H),3.75 -3.71 (m, 1H), 3.17-3.15 (m, 1H), 1.88-1.78 (m, 4H), 1.76-1.72 (m, 4H).

Example 75: (S)-(2-Chloro-4-phenoxyphenyl)(4-(pyrrolidin-3-ylamino)-1H-pyrrolo[2,3-b]pyridin-3-yl ) ketone (I-75)

Compounds were prepared following general scheme 4 using intermediate 8a (Table 1) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (21x) to give the desired product.

MS m/z: 433.1 (M+H) ⁺ .

Example 76: (R)-(2-Chloro-4-phenoxyphenyl)(4-(pyrrolidin-3-ylamino)-1H pyrrolo[2,3-b]pyridin-3-yl) Methyl ketone (I-76)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (21y) to give the desired product.

MS m/z: 33.1 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=8.89 (d, 1H), 8.11 (d, 1H), 7.71 (s, 1H), 7.64-7.56 (m,3H), 7.37-7.33(m,1H), 7.29-7.28(m,3H), 7.14-7.11(m,1H), 6.49(d,1H), 4.47-4.46(m,1H), 3.72 -3.70(m, 1H), 3.16-3.14(m, 4H), 2.54-2.50(m, 1H), 2.10-2.09(m, 1H).

Example 77: (R)-(2-Chloro-4-phenoxyphenyl)(4-((1-(methylsulfonyl)piperidin-3-yl)amino)-1H-pyrrole[2,3 -b]pyridin-3-yl)methanone (I-77)

This compound was prepared according to general formula 8 using intermediate 26 and methylsulfonyl chloride (29b) to give the desired product;

MS m/z: 554 (M+H) ⁺ .

Example 78: (4-(((1r,3r)-3-aminocyclobutyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-benzene Oxyphenyl) ketone (I-78)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate (21aa) to give the desired product;

MS m/z: 433.2 (M+H) ⁺ .

Example 79: (4-(((1s,3s)-3-aminocyclobutyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-benzene Oxyphenyl) ketone (I-79)

This compound was prepared according to general formula 4, using intermediate 8a (Table 1) and tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate (21bb) to give the desired product;

MS m/z: 433.2 (M+H) ⁺ .

Example 80: (4-(((1R,3R)-3-aminocyclopentyl)amino)-1H-pyrro[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy phenyl) ketone (I-80)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl((1R,3R)-3-aminocyclopentyl)carbamate (21cc) to give the desired product;

MS m/z: 447.2 (M+H) ⁺ .

Example 81: (4-((1S,3R)-3-aminocyclopentyl)amino)-1H-pyrro[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy) Phenyl) ketone (I-81)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1R,3S)-3-aminocyclopentyl)carbamate (21dd) to give the desired product;

MS m/z: 447.2 (M+H) ⁺ .

Example 82: (4-(((1R,3R)-3-aminocyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy phenyl) ketone (I-82)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1R,3R)-3-aminocyclohexyl)carbamate (21ee) to give the desired product;

MS m/z: 461.2 (M+H) ⁺ .

Example 83: (4-(((1S,3R)-3-aminocyclohexyl)amino)-1H-pyrrolo[2,3-b]pyridin-3-yl)(2-chloro-4-phenoxy phenyl) ketone (I-83)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1R,3S)-3-aminocyclohexyl)carbamate (21ff) to give the desired product;

MS m/z: 461.2 (M+H) ⁺ .

Example 84: N-((1r,4r)-4-((3-(2-chloro-4-phenoxybenzoyl)-1H-pyrro[2,3-b]pyridin-4-yl) Amino)cyclohexyl)methanesulfonamide (I-84)

This compound was prepared in a manner analogous to general formula 8, using product 1-73 and methanesulfonyl chloride (27b) to give the desired product;

MS m/z: 539.2 (M+H) ⁺ .

Example 85: N-((1s,4s)-4-((3-(2-chloro-4-phenoxybenzoyl)-1H-pyrro[2,3-b]pyridin-4-yl) Amino)cyclohexyl)methanesulfonamide (I-85)

This compound was prepared in a manner analogous to general formula 8, using product 1-74 and methylsulfonyl chloride (27b) to give the desired product;

MS m/z: 539.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=12.5 (s, 1H), 8.85-8.83 (d, 1H), 7.94-7.92 (d, 1H) ,7.57-7.55(m,2H),7.50-7.46(m,2H),7.27-7.23(m,1H),7.19-7.14(m,4H),7.04-7.01(m,1H),6.38-6.36( d, 1H), 3.69 (s, 1H), 3.36 (s, 1H), 2.918 (s, 3H), 1.79-1.75 (m, 8H).

Example 86: N-((1r,4r)-4-(((3-(2-chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) cyclohexyl) acetamide (I-86)

This compound was prepared in a manner analogous to general formula 8, using product 1-73 and acetyl chloride (27c) to give the desired product;

MS m/z: 503.2 (M+H) ⁺ .

Example 87: N-((1s,4s)-4-(((3-(2-chloro-4-phenoxybenzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl ) amino) cyclohexyl) acetamide (I-87)

This compound was prepared in a manner analogous to general formula 8, using product 1-74 and acetyl chloride (27c) to give the desired product;

MS m/z: 503.2 (M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400 MHz): δ=9.52 (s, 1H), 7.79 (d, 1H), 7.42-7.37 (m, 4H), 7.27 -7.23(m,1H),7.10-7.06(m,3H),6.96-6.93(m,1H),6.27(d,1H),5.66(d1H),5.30(s,1H),3.96-3.94(m ,1H),3.81-3.80(m,1H),1.962(s,3H),1.95-1.86(m,2H),1.87-1.80(m,4H),1.76-1.71(m,2H).

Example 88: (2-Chloro-4-phenoxyphenyl)(4-(((1r,4r)-4-(methylamino)cyclohexyl)amino)-1H-pyrrolo[2,3- b]Pyridin-3-yl)methanone (I-88)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1r,4r)-4-aminocyclohexyl)(methyl)carbamate (21 gg) to give the desired product;

MS m/z: 475.2 (M+H) ⁺ .

Example 89: (2-Chloro-4-phenoxyphenyl)(4-((1s,4s)-4-(methylamino)cyclohexyl)amino)-1H-pyrrolo[2,3-b ] Pyridin-3-yl)methanone (I-89)

This compound was prepared according to general formula 4 using intermediate 8a (Table 1) and tert-butyl ((1s,4s)-4-aminocyclohexyl)(methyl)carbamate (21hh) to give the desired product;

MS m/z: 475.2(M+H) ⁺ ; ¹ H NMR (DMSO-d6, 400MHz): δ=12.5(s,br,1H), 8.73-8.71(M,1H), 8.51(s,br, 1H), 7.94-7.92(d, 1H), 7.56-7.53(m, 2H), 7.50-7.46(m, 2H), 7.27-7.23(m, 1H), 7.19-7.17(m, 3H), 7.04- 7.01(m, 1H), 6.33-6.32(d, 1H), 3.78(s, 1H), 3.11(s, 1H), 2.55(s, 3H), 1.93-1.91(m, 4H), 1.77-1.75( m,4H).

Example 90: Biological Activity Studies:

BTK Kinase and BTK C481S Kinase Activity Test:

The inhibitory activity of some compounds of the present invention was determined using the protocol listed below.

The activities of BTK kinase and BTK C481S kinase were determined by mobility transfer assay.

Prepare 1x concentration of kinase buffer. The compound was serially diluted 3-fold with dimethyl sulfoxide, with a total of 10 concentrations (100000, 33333.33, 11111.11, 3703.70, 1234.57, 411.52, 137.17, 45.72, 15.24, 5.08nM) to make a 100-fold final solution. The final starting concentration of test compounds was 1 [mu]M (1000 nM).

Use a dispenser Echo 550 to transfer 250 nL of 100x final concentration of compound to a 384 microwell plate. Dilute with 1-fold concentration of kinase buffer to prepare 2.5-fold final concentration of kinase solution. Add 10 μL of 2.5x final concentration of kinase solution to a 384 microwell plate. Add 10 μL of 1-fold concentration of kinase buffer to the negative control wells. Enzymes and compounds were preincubated for 10 minutes at room temperature. Prepare a mixed solution of ATP and substrate at 5/3x final concentration in 1x kinase buffer. Add 15 μL of a mixed solution of 5/3 times the final concentration of ATP and substrate to the 384-well plate and react at room temperature. The reaction was terminated by adding 30 μL of stop buffer.

Conversions were read with the Caliper EZ Reader II. data analysis

(1) %Inh=(maximum signal−composite signal)/(maximum signal−minimum signal)×100.

(2) In the absence of compound, the maximum signal is obtained.

(3) Min signal was obtained without enzyme action.

Table 1 below lists the _IC50 values for the individual enzymes of the compounds.

Table 1 In vitro inhibition test results of different compounds on the kinases BTK and BTK C481S (unit: nM)

化合物compound	BTKBTK	BTK C481SBTK C481S	化合物compound	BTKBTK	BTK C481SBTK C481S
I-5I-5	9.09.0	1.91.9	I-32I-32	1111	6.26.2
I-6I-6	2.72.7	1.21.2	I-33I-33	8080	3232
I-8I-8	7.17.1	24twenty four	I-35I-35	22twenty two	6.46.4
I-11I-11	6.26.2	3.13.1	I-37I-37	141141	1414

I-22I-22	9.59.5	7.07.0	I-38I-38	242242	2727
I-23I-23	4848	3232	I-40I-40	549549	178178
I-24I-24	5252	1313	I-41I-41	245245	115115
I-28I-28	110110	4747	I-73I-73	1616	5.75.7
I-30I-30	9595	1111	I-74I-74	2.82.8	1.71.7
I-31I-31	2828	1111	I-77I-77	172172	3232
ARQ531ARQ531	9.09.0	2.52.5

Cell Test Experiment:

Plating: Cells were resuspended in serum-free medium and counted using an automated cell counter. Dilute the cell suspension to the desired density according to the seeding density. 95 μL of cells were added to each well (2000 cells/well), 5% CO ₂ , 37°C for stable equilibrium.

Compound preparation: Compounds were prepared into 1000-fold dilution solutions with dimethyl sulfoxide. Compounds were tested at final concentrations of 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51 nM. The compound was then diluted with medium to prepare a compound with a final concentration of 20 times, and 5uL of the compound was added to each well, and the same volume of dimethyl sulfoxide was added to the well as a control, and incubated at 37° C., 5% CO ₂ for 72 hours.

Assay: Equilibrate the cell plate to room temperature and add 40 μL to each well

Reagent, shake for 2 minutes, stand for 10 minutes, and detect with SpectraMax Paradigm.

data analysis:

(1) Calculate IC50 using GraphPad Prism 5;

(2)%Inh=(Max signal-Compound signal)/(Max signal-Min signal) x 100;

(3) Max signal is a positive control well, only the same volume of DMSO as the compound;

(4) Min signal is a negative control well, only medium.

The test results are shown in Table 2:

Table 2 In vitro inhibition test results of different compounds on cells TMD8 and Ba/F3-BCR-BTK-C481S (unit: nM)

化合物compound	TMD8TMD8	Ba/F3-BCR-BTK-C481SBa/F3-BCR-BTK-C481S
I-74I-74	65.9065.90	52.0152.01
I-87I-87	114.20114.20	102.60102.60
I-89I-89	97.6897.68	68.6268.62
ARQ531ARQ531	111.20111.20	447.10447.10

The above are only preferred embodiments of the present invention and are not intended to limit the present invention. It should be pointed out that for those skilled in the art, some improvements can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

The present invention provides compounds of formula I, wherein R, G, W 1 , W 2 , W 3 , X, Y are as defined herein, and their enolates, pharmaceutically acceptable salts, solvates, and compositions thereof,

in:

R is independently selected from substituted or unsubstituted alkyl, alkenyl, alkyl substituted or unsubstituted alcohol, alkyl substituted or unsubstituted amine, substituted or unsubstituted four to seven membered carbocycle, substituted or unsubstituted Four to seven membered carbocyclic rings with heteroatoms including but limited to N, S, O;

G is independently selected from five- or six-membered substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, biphenyl, carbocycle, heteroatom-containing saturated carbocycle or unsaturated carbocycle;

W 1 , W 2 , W 3 are independently selected from CH or N satisfying the valence bond theory;

X is independently selected from O, N, NH;

Y is independently selected from the list below, but is not limited to,

When Y is absent, there is a chemical bond between the G unit and the heteroaryl ring.
A pharmaceutical composition comprising any compound of general formula I, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, hydrate or solvate thereof as claimed in the following item, and a pharmaceutically acceptable compound thereof; acceptable carrier.
The compound of formula I according to claim 1 and its enolate, pharmaceutically acceptable salt, stereoisomer, deuterium substituted derivative, hydrate or solvate, wherein said compound is selected from any of the following examples A sort of:
A pharmaceutical composition comprising a compound or an alkenoate, isomer or pharmaceutically acceptable salt, stereoisomer, deuterium substituted derivative, hydrate or solvate thereof, as claimed in any of claims 1 to 3 A compound in its solvate and a pharmaceutically acceptable carrier or excipient.
Use of any one of the compounds of claims 1 to 3 or the pharmaceutical composition of claim 4 wherein the drug is used alone or in combination with other therapeutic drugs.
One by controlling the kinase activity of Bruton's tyrosine kinase inhibitor or selective for BTK(C481S) mutants or by administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 Or a method of treating a subject suffering from a medicated condition with the pharmaceutical composition of claim 5.
A method of treating a subject having a resistance to a cancer associated with Bruton's tyrosine or BTK(C481S) mutant kinase activity, comprising adding a compound or claim of any one of claims 1 to 5 6. A therapeutically effective amount of the pharmaceutical composition is administered to a subject.
The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, the hydrate or solvate or pharmaceutical composition according to claim 7 , and its preparation purpose is to prevent and/or treat drugs with abnormal BTK activity and diseases related to abnormal activity of BTK mutants (such as C481S).
The medicament or composition of claims 7 and 8 for the treatment of Bruton's tyrosine or BTK(C481S) mutant kinase-related diseases, autoimmune diseases or inflammatory diseases or cancers, including but not limited to B cells Malignant tumor of origin (MCL), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), non-Hodgkin lymphoma (NHL), Waldenstoroms macromyelocytoma (WM) and multiple myeloma (MM) ), intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granuloma.
The use of any one of claims 5 to 9, wherein the medicament is administered orally, parenterally, intravenously or transdermally.